Full Text PA-97-051
 
DEHYDROEPIANDROSTERONE (DHEA) AND AGING: BIOLOGIC ACTIONS AND EFFECTS OF ADMINISTRATION
 
NIH GUIDE, Volume 26, Number 10, March 28, 1997
 
PA NUMBER:  PA-97-051
 
P.T. 34

Keywords: 
  Aging/Gerontology 
  Steroids 
  Physiological Processes 

 
National Institute on Aging
National Institute of Diabetes and Digestive and Kidney Diseases
 
PURPOSE
 
The National Institute on Aging (NIA)and National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK) is interested in
receiving research project grant applications (R01 and R29
mechanisms) addressing gaps in our knowledge of the physiologic roles
and effects of administration of dehydroepiandrosterone (DHEA), or
its sulfated derivative, dehydroepiandrosterone sulfate (DHEA(S), in
middle-aged and older people, and of the mechanism of action of
DHEA(S) at the molecular, cellular and tissue levels. This program
announcement updates and replaces a previous program announcement on
this topic (PA-93-015, Physiological Role of the Adrenal Androgen,
DHEA, in Aging, NIH Guide, v 21, no. 40, November 6, 1992).
 
HEALTHY PEOPLE 2000
 
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People
2000,"a PHS-led national activity for setting priority areas.  This
PA, Dehydroepiandrosterone (DHEA) and Aging, is related to the
priority area of chronic disabling conditions.  Potential applicants
may obtain a copy of "Healthy People 2000" (Full Report: Stock No.
017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through
the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-512-1800).
 
ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by foreign and domestic, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State or local
governments, and eligible agencies of the Federal government. Foreign
institutions are not eligible for First Independent Research Support
and Transition (FIRST) (R29) awards.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as principal investigators.
 
MECHANISM OF SUPPORT
 
Support for this program will be by research project grants (R01) and
FIRST Awards (R29).
 
RESEARCH OBJECTIVES
 
Background
 
Dehydroepiandrosterone (DHEA) is a metabolite on the steroidogenic
pathway between cholesterol and the sex steroids.  In the human and
other primates, the adrenal is the most prolific source of DHEA, with
the sulfated derivative, DHEAS, synthesized primarily in hepatic and
adrenal tissues.  (For the remainder of this Announcement, the
abbreviation DHEA refers to  DHEA and/or DHEA sulfate collectively.)
In primates, DHEA is present in levels considerably higher than the
other steroid metabolites of cholesterol.  Many cross-sectional
studies have documented that serum DHEA levels in humans and other
primates is developmentally regulated, i.e., DHEA increases during
pregnancy to a high level prior to birth, drops precipitously at
birth, increases at adrenarche to a maximum around the early 20's,
then declines gradually into old age (while other major adrenal
steroids, glucocorticoids, remain relatively unchanged with age),
reaching about 10-20% of its peak value around age 80.
 
Clinical and epidemiologic studies on the relationship of DHEA levels
to diseases and other health outcomes have not had consistent
results.  Some prospective studies have found an inverse relationship
between DHEA levels and risk for cardiovascular disease risk in men,
while others have found no relationship.  A case-control study found
low DHEA levels in Alzheimer's disease patients relative to
age-matched controls, while another did not.  Other cross-sectional
studies have reported associations between low DHEA levels and
dyspnea, depressive symptoms, impairments in activities of daily
living in older women (but not men), elevated mortality risk in older
men (but not women), and rheumatoid arthritis, but there have not
been reports of studies to replicate these findings. On the other
hand, a case-control study found higher DHEA levels in cases of
ovarian cancer relative to controls, and two studies found an
association between high DHEA levels and hypertension, while others
found no relationship.  Most of these studies had very limited power
to address the potential confounding effects of covariates which
could contribute to spurious associations (or lack of association)
between DHEA levels and the outcomes reported.
 
Animal studies, generally performed in species in which endogenous
DHEA levels are normally relatively low and may not change
substantially with age, and involving dietary DHEA at very high
levels for most studies, show delayed tumor formation, prevention of
atherosclerosis, weight loss in obese animals and, in general,
retardation of the development of many chronic age-related pathologic
changes.
 
The conference "Dehydroepiandrosterone (DHEA) and Aging", supported
in part by the NIH and sponsored by the New York Academy of Sciences,
was held in Washington, DC in June, 1995 (Bellino, FL, Daynes, RA,
Hornsby, PJ, Lavrin, DH and Nestler, JE, eds. Annals of the New York
Academy of Sciences, vol 774, New York, 1995). The purpose of the
conference was to define a future research agenda based on a review
of the current status of a variety of ongoing investigations into a)
mechanisms of the apparent steady decline of DHEA with age from the
mid-twenties to old age, b) epidemiologic studies suggesting positive
health benefits for individuals with higher levels of DHEA for their
age group and clinical studies of effects in individuals supplemented
with DHEA in the short-term studies, and c) health effects of
supplementary DHEA in animal studies.
 
Goals of the Program Announcement
 
Research on the role of age-related alterations in levels of DHEA,
and its metabolites, is currently hampered by a lack of information
on certain key issues:
 
1) There is limited information available regarding the biological
role of DHEA, whether produced endogenously or administered
exogenously,  and of its metabolites, and the molecular and cellular
mechanism(s) of action of the active compound(s). This has hampered
epidemiologic, clinical and animal studies on DHEA and aging.
 
2) Clinical intervention studies to date have rarely been repeated by
other investigators, and have not systematically examined the various
subgroups (e.g., of gender, age, or DHEA levels) in the older
population to determine which, if any, show responses to DHEA
administration. Studies to date have provided very limited
dose-response and time-course information.
 
In order to facilitate and guide further mechanistic and applied
studies related to DHEA and aging, this program announcement solicits
high quality research that fills these gaps in knowledge. Although
the ultimate goal of this program announcement is focused on human
studies, the use of appropriate animal models, and in vitro human
cell and tissue culture models will also be essential to define the
active form(s) and molecular and cellular mechanism(s) of action.
This information will be valuable for the design of better human
intervention studies.
 
This announcement encourages research in the following areas:
 
1. DHEA BIOLOGIC ACTIONS AND ACTIVE SPECIES: Studies in animals and
humans have demonstrated  a) the requirement for large
(pharmacologic) doses of dietary DHEA for effectiveness in most
rodent studies, b) the presence of DHEA metabolic enzymes in various
body tissues, including non-steroidogenic peripheral tissues, c) the
different profile of DHEA biosynthesis, metabolism and age-dependent
serum pattern in non-primates relative to primates, and d) lack of
attention to DHEA metabolism on the effects and mechanism of action
of DHEA in animals or humans.  For these reasons, it is important to
characterize the biologic effects of DHEA and its metabolites more
fully, and determine the active form(s) of DHEA or its metabolites
responsible for them. Once defined, more directed molecular and
cellular mechanism of action studies can be accomplished.  One
approach, already utilized to some extent, might be to utilize
non-metabolizable analogs of DHEA or specific metabolites to
determine the extent of their contribution to specific biologic
effects.
 
Research questions of interest include, but are not limited to:
 
o What are the bioactive form(s) of DHEA; are there separate active
forms depending on the effect sought?
 
o What are the roles of sulfatase and sulfotransferase in DHEA
action?
 
2. DHEA MECHANISM OF ACTION: Potential mechanisms of action for DHEA
are extensive. The range of projected actions is so wide (brain,
cardiovascular and immune system effects, anti-cancer or carcinogenic
(depending on dose), anti-obesity, bone protective, etc.), it raises
the question of whether a single compound is responsible for all of
the actions.  Ongoing studies suggest several mechanisms of action:
a) as a non-competitive inhibitor of glucose 6-phosphate
dehydrogenase (G6PD), the rate-limiting enzyme in the pentose
phosphate pathway which provides ribose 5-phosphate and NADPH, b) as
a "neurosteroid" through interactions with neuronal GABA and sigma
receptors, c)  through regulation of enzyme activity or bioregulatory
factors and their receptors (e.g., enoyl CoA hydratase,
carbomylphosphate synthetase, malic enzyme, glycerol-3- phosphate
dehydrogenase, T cell IgD receptor, cytokines), or d) through
regulation of gene expression (e.g., various cytochrome P450s,
NADPH-cytochrome P450 reductase, fatty acyl CoA oxidase). There are a
small number of reports in the literature of 'receptors' for DHEA,
but as yet no study has unequivocally identified these DHEA 'binding
proteins' as nuclear transcription factors.
 
Research questions of interest include, but are not limited to:
 
o What are specific molecular mechanisms of action of the active
form(s) of DHEA, i.e., interactions with receptors, nuclear
transcription factors and/or signal transduction pathways?
 
o To what extent and by what mechanisms do biologic effects in animal
studies translate to human cells, tissues and the entire organism?
 
o The Endocrinology Research Programs at NIDDK focus on the molecular
endocrinology of hormones, growth factors, and cytokines. In
particular, support for research on the steroid/thyroid/retinoid
supergene family of hormones and their receptors is an important part
of the NIDDK mission.  Additional areas of concern include the
hypothalamic-pituitary-adrenal axis with regard to response to
stress, regulation of body composition, and interaction with the
neuroendocrine and immune systems.  NIDDK would welcome any
submissions in response to this PA which are relevant to its mission,
including:
 
o Fundamental questions of the role of DHEA in the regulation of gene
expression in target tissues
 
o Identification and characterization of putative DHEA receptor(s)
 
0 Cross-talk between DHEA and other hormones, including questions
related to signal transduction.
 
3. CLINICAL ISSUES.  Background:  Whether the decline in serum DHEA
levels in humans with age has any relevance to the occurrence of
chronic or acute health problems in older people is still an open
question.  Even if a strong and specific association of health
problems with serum DHEA levels is demonstrated, are those health
problems reversible or preventible with the active form(s) of DHEA
through supplementation?
 
DHEA has been used in controlled human studies at doses up to 1600
mg/day for four weeks, and at much lower doses (50 mg/day) for as
long as six months, in subjects up to age 70. No apparent significant
adverse effects have been reported. These studies have reported
effects suggesting potential therapeutic benefits from DHEA:
preservation of insulin sensitivity in post-menopausal women,
increased muscle mass and strength, and decreased fat mass in men
(but not in women) and decreased platelet aggregability.
 
These results suggest that administration of DHEA to certain
individuals might aid in preventing or treating several important
age-associated conditions, disabilities, and risk factors: prevention
of non insulin-dependent diabetes mellitus, maintenance of muscle
function, prevention of obesity, and prevention of thrombotic events
such as myocardial infarction and thrombotic stroke.
 
However, the value of intervention trials to determine the effects of
DHEA administration on these clinical outcomes will remain unclear
without clarification of several issues.  All the above studies
involved small numbers of subjects, and (with the exception of the
studies on fat mass), have not been followed by reports of
replication studies from other research groups. In addition, several
were confined to one gender only.  Potential adverse effects of DHEA
administration have not been systematically explored. For example,
the potential for DHEA to be metabolized to androgens and estrogens
could have both beneficial and adverse effects. If indeed DHEA has
antithrombotic and fibrinolytic effects which might lessen risk for
thrombotic events or their consequences, these could also increase
risk for hemorrhagic events.
 
Additional ambiguities stem from the fact that most of these
intervention studies did not address the degree of metabolism of DHEA
to other steroids, administration of these metabolites as additional
controls,  dose-response studies, analysis in relation to subjects'
DHEA level and age at the beginning of treatment, and effects of
different schedules of DHEA administration.
 
Clinical Studies Solicited by this Announcement: As reviewed in the
foregoing sections,  a variety of epidemiologic, biologic, and
clinical studies suggest that DHEA may have effects on age-related
health outcomes, but do not in themselves provide a strong rationale
for clinical trials to test effects of DHEA administration to these
outcomes, nor provide the information to determine what the most
suitable subjects, dosages  and outcomes for testing would be, were
such trials warranted.  Thus, to determine whether there is a
rationale for clinical trials of effects of DHEA administration on
age-related health outcomes, and if so, the most suitable designs for
such trials, this Announcement solicits clinical intervention studies
to address issues such as the following.
 
o  Relationships of  physiologic and functional responses to DHEA
and/or DHEA analogues to: age  (including very advanced age), gender,
levels of DHEA and other hormones before starting administration of
DHEA, and duration, dosage  and scheduling of DHEA (or DHEA analog)
administration.
 
o  Circulating levels of DHEA, (or the DHEA analogue administered),
key active metabolites, and other relevant circulating hormones, over
the course of  intervention, and their relationships to observed
effects.  Inclusion of additional intervention arms using possible
active DHEA metabolites such as gonadal steroids, or non-
metabolizable DHEA derivatives, may also be useful in addressing this
point.
 
o  Potential adverse effects, including those which might be
anticipated from  DHEA metabolites. In addition to monitoring adverse
clinical events per se, measurements of risk factors or physiologic
indicators which indicate risk for such events are important.
 
o  Effects ascribed to DHEA in other studies, to test the
replicability of these findings.
 
(It is not required that each application submitted in response to
this Announcement must address ALL the variables outlined in the
above topics.  The range and selection of variables to be studied is
at the discretion of the applicant.)
 
Additional research questions of interest include, but are not
limited to:
 
o  If circulating DHEA is not the primary active form in humans, does
the decline of circulating DHEA with age in humans reflect a decline
in the true active form(s)?  If not, what, if anything, is a valid
marker of "DHEA" status?
 
o  Since longitudinal studies suggest that the age-related decline of
serum DHEA in humans is not universal, does maintenance of endogenous
circulating DHEA levels through old age contribute to maintenance of
health or functional status?  Related to this, is there a DHEA
deficiency state or syndrome that would help in sorting out biologic
effects in humans?
 
o  What accounts for the gender effects in epidemiologic and clinical
DHEA research?
 
In addition to the award mechanisms listed above under "Mechanisms of
Support", prospective applicants with research interests in the
topics listed above under "Clinical Studies Solicited by this
Announcement" may wish to consider two additional funding mechanisms:
Up to $50,000 (direct costs) for pilot studies on these topics may be
requested through NIA Pilot Grants (R03) in Geriatrics (PAR-97-041,
NIH Guide to Grants and Contracts, Vol. 26, No. 7, March 7, 1997.  Up
to $100,000 (direct costs) in support for planning efforts to develop
research projects on these topics may be requested through NIA
Planning Grants for Biomedical Epidemiologic and Intervention Studies
(PAR-97-011, NIH Guide to Grants and Contracts, Vol. 25, #39,
November 15, 1996).  Announcements describing these two award
mechanisms are available on the NIA Home Page
(http://www.nih.gov/nia/) or from the NIA Geriatrics Program (FAX
301-402-1784, or E-mail: solomonw@gw.nia.nih.gov).
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43).
 
All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH
Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit. Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive MSC
7910, Bethesda, MD 20892-7910, telephone 301/710-0267; email:
asknih@odrockm1.od.nih.gov.  The title and number of the program
announcement must be typed in Section 2 on the face page of the
application.
 
Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
 
The completed original application and five legible copies must be
sent or delivered to:
 
Division of Research Grants
National Institutes of Health
6701 Rockledge Drive, Room 1040 - MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for courier/overnight mail service)
 
REVIEW CONSIDERATIONS
 
Applications will be assigned on the basis of established Public
Health Service referral guidelines.  Applications will be reviewed
for scientific and technical merit by study sections of the Division
of Research Grants, NIH, in accordance with the standard NIH peer
review procedures.  Following scientific-technical review, the
applications will receive a second-level review by the appropriate
national advisory council.
 
Review Criteria
 
o  scientific, technical, or medical significance and originality of
proposed research;
 
o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;
 
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;
 
o  availability of the resources necessary to perform the research;
 
o  appropriateness of the proposed budget and duration in relation to
the proposed research;
 
o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects, the safety of the research
environment.
 
AWARD CRITERIA
 
Applications will compete for available funds with all other approved
applications assigned to the NIA.  The following will be considered
in making funding decisions:  Quality of the proposed project as
determined by peer review, availability of funds, and program
priority.
 
INQUIRIES
 
Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Frank Bellino, PhD
Biology of Aging Program
National Institute on Aging
Gateway Building, Suite 2C231
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email:  bellinof@gw.nia.nih.gov
 
Evan Hadley, MD
Geriatrics Program
National Institute on Aging
Gateway Building, Suite 3E327
Bethesda, MD  20892-9205
Telephone:  (301) 435-3044
FAX:  (301) 402-1784
Email:  hadleye@gw.nia.nih.gov
 
For inquiries related to the mission of the NIDDK:
 
Ronald N. Margolis, PhD
Chief, Endocrinology Section
NIDDK
Building 45, Room 5AN-12J
45 Center Dr.
Bethesda, MD 20892-6600
Telephone: (301) 594-8819
FAX: (301) 480-3503
Email: rm76f@nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Robert Pike
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
Bethesda, MD  20892
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
email: pikeb@gw.nia.nih.gov
 
Kim Law
Grants Management Specialist
Building 45, Room 6AS-49A
NIDDK
45 Center Dr.
Bethesda, MD 20892-6600
Telephone: (301) 594-8869
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.866, Aging Research, and 93.847, Diabetes and
Digestive and Kidney Disease Research.  Awards are made under
authorization of the Public Health Service Act, Title IV, Part A
(Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and
285) and administered under PHS grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not
subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency review.
 
The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routine education,
library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS
mission to protect and advance the physical and mental health of the
American people.
 
.

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